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Key Points

Other risk factors for CV disease are common in HIV-infected populations:

Other metabolic abnormalities (eg, insulin resistance and diabetes, which may be caused or exacerbated by ARV medications)

Hypertension

Smoking

Inactivity

Patients should be treated for dyslipidemia based on their lipid levels and other risk factors for CV disease.

LDL cholesterol is the primary target for lipid-lowering therapy.

Some lipid-lowering medications are contraindicated for use with ARV medications, and others require dosage adjustment.

Background

Dyslipidemia is an important risk factor for CV disease, and occurs in a high proportion of people with HIV infection. As advances in ART extend the life spans of people with HIV infection, it is likely that morbidity and mortality from CV disease will increase. It is important to identify patients' CV risk factors and to reduce those that are modifiable.

CV risk is associated with:

Elevated LDL and TC

Low HDL

Elevated TG

Of these, elevated LDL is most closely linked to CV risk, and usually is the primary target of therapeutic interventions.

Dyslipidemia is associated both with HIV infection itself and with ARV medications. Accumulating data suggest that both HIV infection and certain ARV medications may increase the risk of CV disease, independent of their effects on lipids.

Stigmata of hyperlipidemia and hypertriglyceridemia: xanthelasma and tendon xanthomas, which are associated with extremely elevated LDL levels; eruptive xanthomas and hepatomegaly, which may be present in the setting of extremely elevated TG levels (chylomicronemia)

Determine whether intervention is needed according to the patient's lipid values and CHD risks, following these 3 steps. Note that for most patients, LDL is the main indicator of need for lipid-lowering therapy.

The NCEP also recommends estimating the patient's 10-year risk of MI using the assessment tool derived from the Framingham Heart Study . Note that this tool does not estimate lifetime risk of MI, which for many patients is substantially higher than their 10-year risk. Intervention to treat lipid abnormalities may be warranted even in patients with a low 10-year risk, to prevent CV events later in life.

If TG is >400 mg/dL, the LDL cholesterol calculation is unreliable. Use non-HDL cholesterol as a surrogate target of therapy (non-HDL = TC - HDL); the non-HDL goal is 30 mg/dL higher than the LDL goal.

If TG is 200-500 mg/dL, LDL is the primary target of initial therapy (see Table 1 for LDL intervention levels); if TG is ≥500 mg/dL, TG may be the initial target of therapy (see below).

Hypertriglyceridemia is associated with CAD risk, but it is unclear whether it is an independent risk factor; hence indications for treatment are less certain than those for cholesterol abnormalities.

Management

The primary goal of lipid-lowering therapy for most patients is to lower LDL to target levels. The potential benefits of lipid-lowering therapy for HIV-infected patients should be balanced against drug toxicities, as well as the risk of CV mortality relative to HIV-associated mortality.

If the TG level is very high, it may have to be reduced before LDL is treated directly (see below).

Low HDL is not usually a primary target of therapy; data are conflicting as to whether raising HDL confers CV benefits.

A multimodal approach to treatment is important:

Lifestyle modification

Lipid-modifying medication

Changes in ARV medication (or other exacerbating medication), if possible

Management of associated conditions (eg, diabetes)

See Table 1 for LDL levels at which either TLC or drug therapy should be initiated, and for the target goals for LDL cholesterol.

Lifestyle Modification

Lifestyle modification is fundamental to the management of dyslipidemia and should be initiated in all patients with dyslipidemia. Behavioral changes may be difficult for patients, but can yield significant results in improving lipid values and reducing CHD risk.

Encourage patients to:

Reduce dietary cholesterol and saturated fat (all patients)

If overweight, lose weight

Maintain or increase aerobic exercise (all patients)

Reduce alcohol consumption (especially for those with high TGs)

Stop smoking, and reduce other CHD risk factors

Medication

See Table 3 and Characteristics of Lipid-Lowering Medications, below, for information about lipid-lowering medications. Therapies should be intensified or augmented until lipid targets are met.

Many have significant drug interactions with PIs and NNRTIs; some combinations are contraindicated (see Lipid-Lowering Medications). Possible adverse effects include, GI disturbance, myopathy, rhabdomyolysis, liver toxicity (check LFTs 1 month after initiating, then every 3 months). Contraindicated in women who are pregnant or nursing; use caution in patients with active or chronic liver disease.

Recommended starting dosages of statins for patients taking PIs:

Pravastatin: 20 mg PO QD

Fluvastatin: 20 mg PO QD

Atorvastatin: 10 mg PO QD

Rosuvastatin: 5-10 mg PO QD

When given concomitantly, statins and fibrates increase the risk of rhabdomyolysis; in general, this combination should be avoided.

Fibrates: Decrease TG and increase HDL; modestly decrease LDL. Gemfibrozil has been shown to reduce risk of CV events (in HIV-uninfected individuals); fenofibrate has not. In one study, clofibrate was associated with increased risk of noncardiac mortality. An option for initial treatment of isolated hypertriglyceridemia and an alternative treatment for combined hypertriglyceridemia and hypercholesterolemia.

Not metabolized by the cytochrome P450 hepatic enzyme system; no significant drug interactions with ARVs (an exception is LPV/r, which reduces gemfibrozil levels). Contraindicated in severe renal or hepatic disease. Fibrates generally should not be used with statins because of increased risk of myositis. Other possible adverse effects: GI disturbance, gallstones, dizziness. Recommended dosages:

Bile acid sequestrants: Generally should be avoided unless no other options; may interfere with the absorption of other drugs (including ARVs), and may increase TG levels.

Ezetimibe: Has not been studied thoroughly in HIV-infected individuals, but appears to be effective in lowering TC and LDL. However, because of lack of data showing that ezetimibe decreases CV events, it should not generally be used as monotherapy. Usually used in combination with statins if LDL is not controlled adequately with a statin alone. Contraindicated in patients with liver disease.

Switching ARVs

For patients with CHD or CHD equivalents, try to select ARV medications associated with the lowest risk of dyslipidemia.

For example, substitute ATV, RAL, or NVP in place of a lipogenic PI or substitute an unboosted PI (eg, ATV or FPV) for an RTV-boosted PI.

Replace d4T with TDF, or perhaps ABC*.

Before making ARV substitutions, consider the possible effect on HIV virologic control and the potential adverse effects of new ARVs.

In some cases, antihyperlipidemic agents may still be necessary after ARV substitution.

* Data from the D:A:D observational study associated ABC with increased risk of MI; some other studies have not confirmed this association. See References.

Potential ARV Interactions

Interactions with ARVs: Most PIs inhibit the metabolism of most statins and can significantly increase serum statin levels, thus increasing the risk of toxicity, including rhabdomyolysis.

Some combinations are contraindicated. Of the statin drugs, pravastatin is the least affected by most PIs (DRV is an exception). Atorvastatin, if used, must be initiated cautiously and at a low dose. EFV can induce the metabolism of some statins, causing therapeutically significant decreases in their concentrations. See Lipid-Lowering Medications, for further information.